JP5650208B2 - Composition for treating drug addiction and improving addiction related behavior - Google Patents

Description

  The present invention relates to the use of carbamate compounds alone or in combination with other drugs to treat addiction to drugs of abuse, particularly opioids, and behavioral changes associated with drug addiction. Specifically, the present invention relates to a pharmaceutical composition comprising a carbamate compound alone or in combination with other drugs, or a carbamate compound alone, for treating drug addiction or behavioral changes associated with drug addiction or drug abuse. Or relates to a method of use in combination with other drugs.

  Substance addiction such as drug abuse and addiction-related behavior resulting from it have become major socio-economic problems, the number of which continues to increase and have disastrous consequences.

  Abuse drugs such as cocaine, nicotine, methamphetamine, morphine, heroin, ethanol, phencyclidine, methylenedioxymethamphetamine, and other drugs of abuse have a tendency to addiction to the central nervous system (CNS) telencephalon center dopamine (DA) These drugs have been linked to exerting a pharmacological action against the enhancement / reward pathways (mesoencephalic dopamine reinforcement / reward pathway). Dopaminergic transmission in this pathway is regulated by γ-aminobutyric acid (GABA).

  Almost all drugs of abuse, including nicotine, have been shown to rapidly increase extracellular dopamine levels in the nucleus accumbens of mammals. This increase is clearly associated with the addictive tendency of these compounds. Based on this unique biochemical feature, drugs that alleviate or eliminate this response are considered very effective in treating substance abuse.

  Substance addiction can be caused by the use of both legal and illegal substances. Nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA), and other addictive substances are readily available and customary by many Americans Have been used.

  Many of the drugs of abuse are naturally derived. For example, cocaine is a natural non-amphetamine stimulant derived from the leaves of a coca plant, ie, Erythrolon coca. Coca leaves contain only about half of 1% pure cocaine alkaloids. Chewing a coca leaf releases only a relatively small amount of cocaine and is slow to absorb in the digestive tract. This clearly explains why the habit of chewing in Latin America did not become a public health problem. With the abuse of the alkaloid itself, things are completely different.

  Addictive drugs such as nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine, and methylenedioxymethamphetamine are used in the telencephalic central reward / enhancement circuit (sometimes directly, sometimes It is known that some dopamine (DA) increases indirectly or transsynaptically, but this increases the reward system of the brain and presumes that the drug user will be “high” Is done.

  In drug cravings and recurrence of drug intake habits in addicting addictions, functional changes in the DA system have also been suggested. For example, cocaine acts on the DA system by binding to the dopamine transporter (DAT) and preventing DA reuptake into the presynaptic terminal.

  Addiction blockade in nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine, methylenedioxymethamphetamine, and other drugs of abuse, and reuptake blockade in the CNS reward / enhancement pathway There is a lot of evidence that links For example, in rodents, the increase in extracellular DA induced by cocaine is associated with reward and craving effects.

In humans, the pharmacokinetic binding profile of ¹¹ C-cocaine shows a direct correlation between labeled cocaine uptake and self-reported “high”. Moreover, cocaine addicts exposed to environmental stimuli associated with cocaine experience an increased craving for cocaine that antagonizes the DA receptor antagonist haloperidol. Numerous pharmacological strategies have been proposed to treat addiction to cocaine based on the presumed causal relationship between the addiction tendency of cocaine and the forebrain DA reward / enhancement circuit.

  One previously proposed treatment strategy has been to directly target DAT with high affinity cocaine analogs, thereby blocking cocaine binding. Another therapeutic strategy has been to directly modulate synaptic DA by using DA agonists or DA antagonists. Yet another therapeutic strategy is to regulate synaptic DA indirectly or transsynaptically by targeting specific neurotransmitter systems that are biochemically different but functionally related. there were.

  Numerous drugs have been proposed to withdraw cocaine users from addiction. Some therapeutics were supported by the “dopamine depletion hypothesis”. It is well documented that cocaine blocks dopamine reuptake and rapidly increases synaptic dopamine levels. However, in the presence of cocaine, synaptic dopamine is metabolized and excreted as 3-methoxytyramine. As supported by the increase in tyrosine hydroxylase activity after cocaine administration, the disappearance of dopamine at the synapse promotes enhanced synthesis of dopamine in the body. When the source of dopamine precursor is exhausted, dopamine deficiency develops.

  Based on the above hypothesis, bromocriptine, which is a dopamine receptor agonist, was evaluated. As another method, amantadine, a dopamine-releasing drug, was administered. Yet another method based on the dopamine depletion hypothesis was to supply dopamine precursors such as L-dopa.

  Agonists are not preferred as therapeutic agents. Certain agonists may act not only on the specific receptor or cells on which stimulation is desired, but also on multiple types of receptors or similar receptors on different cells. Just as resistance to drugs is formed (by changing the number of receptors and the affinity of receptors for drugs), resistance to agonists can be formed. Problems with the agonist bromocriptine include, for example, the potential for drug dependence itself. Thus, the treatment strategies used in the past have not been able to reduce the patient's craving for cocaine. Furthermore, the use of certain agonists such as bromocriptine tended to switch the subject of patient craving from cocaine to agonist.

  Another drug that is frequently abused is nicotine. The alkaloid (−)-nicotine is present in cigarettes and other tobacco products for smoking or chewing. Nicotine has been found to contribute to various diseases, particularly heart disease, including cancer, heart disease, respiratory disease, and other conditions where tobacco use is a risk factor.

  It is now well-known fact that campaigns against tobacco and nicotine consumption are active, and that many uncomfortable withdrawal symptoms occur with the cessation of tobacco use. Such withdrawal symptoms include shortness, anxiety, restlessness, lack of concentration, dizziness, insomnia, trembling, increased hunger, and weight gain, including intense craving for tobacco. Needless to say.

  The addictive tendency of nicotine has been associated with reward / reinforcement and effects of brain reward pathways on DA neurons (Nisell et al., 1995; Pontieri, et al., 1996). For example, like many other drugs of abuse, acute systemic administration of nicotine increases extracellular DA levels in the nucleus accumbens (NACC), an important component of the reward system (Damsma et al., 1989 Di Chiara and Imperato, 1988; Imperato et al., 1986; Nisell et al., 1994a, 1995; Pontieri et al., 1996). Similarly, infusion of nicotine into the rodent ventral tegmental area (VTA) of rodents also significantly increases DA levels in NACC (Nisell et al., 1994b).

  Several medications have been reported as useful for treating nicotine addiction, including nicotine gum, transdermal nicotine patch, spray nasal spray, nicotine inhaler, and first non-nicotine smoking cessation. Included are nicotine replacement therapies such as the therapeutic drug bupropion (Henningfield, 1995; Hurt, et al., 1997).

  Unfortunately, nicotine replacement therapy frequently involves nicotine withdrawal symptoms and subsequent reversion to tobacco product use, as it involves the administration of nicotine. Accordingly, there is a need for a treatment with a desirable side effect profile to reduce nicotine withdrawal symptoms, including long-term craving for nicotine.

  Other well-known addictive substances are narcotic analgesics such as morphine, heroin, and other natural and semi-synthetic opioids. Opioid abuse causes tolerance and dependence. The strength of withdrawal symptoms due to opioid discontinuation depends on the dose of opioid, the degree of opioid action continuously exerted on the CNS, the period of chronic use, and the rate of dissociation of the opioid from the receptor. Varies depending on a number of factors including.

  These withdrawal symptoms include cravings, anxiety, discomfort, lack of growth, sweating, lacrimation, nasal discharge, restlessness, choppy sleep, shortness of breath, dilated pupils, bone / back / muscle pain, hair growth, hot flashes Chills, nausea, vomiting, diarrhea, weight loss, fever, elevated blood pressure, tachycardia, tachypnea, muscle twitches, and leg kicking.

  Medical complications associated with opioid injection include various pathological changes in the CNS, including degenerative changes in the pallidum, necrosis of spinal cord gray matter, transverse myelitis, amblyopia, plexitis, peripheral neuropathy , Parkinsonism, intelligence impairment, personality changes, and pathological changes in muscle and peripheral nerves. In addition, infections of the skin and systemic organs are very common and include staphylococcal interstitial pneumonia, tuberculosis, endocarditis, sepsis, viral hepatitis, human immunodeficiency virus (HIV), malaria, tetanus, and Includes osteomyelitis. The life expectancy of opioid addicts is significantly shortened due to overdose, drug-related infections, suicide, and murder.

  Examples of pharmaceuticals used for the treatment of opioid dependence include methadone, which is a kind of opioid, and opioid antagonists mainly composed of naloxone and naltrexone. Clonidine has been shown to suppress some of the symptoms of opioid withdrawal, but it can cause side effects such as hypotension and sedation, which can be extreme. Psychotherapy and training to correct behavior are often adjunct therapies along with medical treatment. In order to reduce opioid addiction and its withdrawal symptoms, there is a need for a treatment with a more desirable side effect profile.

  Ethanol is probably the most frequently used and abused suppressant in most cultural spheres and is a major cause of morbidity and mortality. Repeated intake of large amounts of ethanol can affect almost every organ system of the body, especially the gastrointestinal tract, circulatory system, central nervous system, and peripheral nervous system. Actions on the gastrointestinal tract include gastritis, gastric ulcer, duodenal ulcer, cirrhosis, and pancreatitis.

  In addition, ethanol abuse increases the incidence of esophageal cancer, gastric cancer, and cancer in other parts of the gastrointestinal tract. Actions on the cardiovascular system include hypertension, cardiomyopathy, and other muscle diseases in which triglyceride levels and low density lipoprotein cholesterol levels are significantly elevated. These cardiovascular effects significantly increase the risk of heart disease.

  Ethanol abuse can manifest as peripheral neuropathy, as evidenced by muscle weakness, sensory abnormalities, and loss of peripheral sensation. Effects on the central nervous system include cognitive impairment, severe memory impairment, degenerative changes in the cerebellum, and ethanol-induced persistent amnesia disorder that significantly impairs the coding function of new memory. In general, these effects are associated with vitamin deficiencies, particularly vitamin B deficiency.

  Patients with ethanol dependence or ethanol addiction may have dyspepsia, nausea, bloating, esophageal varices, hemorrhoids, tremors, unstable gait, insomnia, erectile dysfunction, testicular atrophy, feminization related to decreased testosterone levels, spontaneous abortion, Symptoms and physical changes, including fetal alcohol syndrome. Symptoms associated with ethanol withdrawal or withdrawal include nausea, vomiting, gastritis, vomiting, dry mouth, spotted and swollen facial features, and peripheral edema.

  The generally accepted treatment for ethanol addiction and withdrawal is achieved by administration of moderate tranquilizers such as chlordiazepoxide. Typically vitamins, especially vitamin B, are also administered. Optionally, magnesium sulfate and / or glucose is also administered. Nausea, vomiting, and diarrhea are treated symptomatically at the discretion of the attending physician. Disulfiram may be administered to assist in continuing cessation of alcohol. If you take ethanol while taking disulfiram, acetaldehyde accumulates, causing nausea and hypotension. To alleviate ethanol addiction and its withdrawal symptoms, there is a need for a treatment with a more desirable side effect profile.

  Recently, it has been reported that the use of multiple drugs or abuse of mixed drugs is increasing at a alarming rate. For example, cocaine and heroin are often combined and abused in the form of a mixed drug known as a “speedball”. Such an increase in use is thought to be due to a synergistic effect that increases the euphoria of the user.

  In many cases, drug dealers combine various drugs of abuse to increase the “high” intensity. This is particularly done when regular narcotic drug users have developed resistance to a single drug. Drug users are often unaware of the dangers of combining such drugs.

  The action of phencyclidine, commonly known as PCP, is described as dissociative. This means that the spirit feels separated from the body. PCP was first used as a surgical anesthetic in the 1950s. Discontinued due to very harmful side effects such as convulsions and hallucinations.

  The illegal use of PCP was first reported in the late 1960s. However, PCP has lost popularity due to numerous bad experiences reported. In the 1970s, PCP began to be used again naturally, combined with other illegal drugs such as marijuana and cocaine. PCP is still one of the abused substances. Many who have used PCP once will never try to use PCP again. On the other hand, some people use PCP regularly. PCP regular users cite mental and physical painlessness as one of the reasons for using PCP.

  PCP is a synthetic material that can take the form of a pill, powder, or liquid suspension. PCP can be smoked, nasal inhalation, ingested or administered intravenously. The short-term effects of PCP last for hours or days and include respiratory distress, increased blood pressure, increased heart rate, increased body temperature, heavy sweating, strange posture, and muscle spasms. High doses can cause vomiting, visual impairment, seizures, and coma.

  The long-term effects of PCP include flashback, speech impairment, memory loss, anxiety, depression, and social withdrawal. It has been reported by regular users that it is necessary to increase the intake to maintain "high". There is no generally accepted cure for PCP abuse.

  Methylenedioxymethamphetamine (MDMA), commonly known as “ecstasy”, is a synthetic psychotropic drug with excitability and hallucinogenicity. MDMA was first synthesized in 1912 as an appetite suppressant candidate. The illegal use of MDMA began to become popular in the late 1980s.

  MDMA is usually taken orally and the effect can last for 4-6 hours. According to users, using MDMA makes you feel very positive and extremely relaxing. Furthermore, MDMA is said to suppress the desire to eat, drink and sleep. Therefore, the use of MDMA can lead to severe dehydration and extreme fatigue.

  MDMA users may encounter problems similar to those faced by amphetamine users and cocaine users, including addiction. In addition, MDMA can cause confusion, depression, sleep disorders, anxiety, and paranoia. Physical effects from the use of MDMA include muscle tone, unconscious bruxism, nausea, visual impairment, fainting dizziness, and chills or sweating.

  The impact of long-term use of MDMA is just beginning to be scientifically analyzed. The National Institute of Mental Health conducted research on MDMA addicts in 1998 and found that neurons in the brain that transmit serotonin are damaged. Serotonin is an important biochemical that is associated with a variety of critical functions including learning, sleep, and emotional integration. The results of the above studies indicate that MDMA users are at increased risk for permanent brain damage that can manifest as depression, anxiety, memory loss, and other neuropsychiatric disorders. There is no generally accepted treatment for MDMA abuse.

  Therefore, in the treatment of abused drug addiction, there is a need to provide a novel method that can reduce patient craving by changing the pharmacological action of abused drugs in the central nervous system. Further, there is a need to provide new methods for treating abuse of mixed drugs.

The present invention relates to structural formula (I):
Wherein R is hydrogen; lower alkyl having 1 to 8 carbon atoms; halogen selected from F, Cl, Br, and I; alkoxy having 1 to 3 carbon atoms; nitro group; hydroxy; trifluoromethyl And selected from the group consisting of thioalkoxy having 1 to 3 carbon atoms;
x is an integer from 1 to 3, but when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different and are each selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, and cycloalkyl having 3 to 7 carbon atoms;
R ₁ and R ₂ may combine to form a 5- to 7-membered heterocyclic ring substituted with a substituent selected from the group consisting of hydrogen, an alkyl group, and an aryl group. 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, the nitrogen atoms not being directly bonded to each other or to the oxygen atoms)
Or a pharmaceutically acceptable salt or ester thereof is administered to a mammal in need of treatment for a method of treating drug addiction.

  In yet another embodiment, the present invention provides a method of improving abuse related drug addiction related behavior in a subject, wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof is A method is provided that includes administering to a subject in need of treatment.

  In yet another embodiment, the present invention provides a method of alleviating or eliminating the effects of abuse drug addiction in a subject comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. Methods are provided that include administering to a subject in need of such treatment.

  In a further embodiment, the present invention relates to a pharmaceutical composition for treating drug addiction comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

  In yet another embodiment, the present invention provides a pharmaceutical composition for improving abuse drug addiction related behavior in a subject comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. I will provide a.

  In yet another embodiment, the invention provides a medicament for alleviating or eliminating the effects of abused drug addiction in a subject comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. A composition is provided.

  In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof for the treatment of drug addiction.

  In yet another embodiment, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof for improving abuse drug addiction related behavior in a subject.

  In a further embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof to mitigate or eliminate the effects of abused drug addiction in a subject.

  The compound having the structural formula (I) is an enantiomer substantially free of other enantiomers or an enantiomeric mixture in which one enantiomer of the compound having the structural formula (I) is predominant. One enantiomer accounts for about 90% or more, preferably about 98% or more of the total.

The enantiomer has the structural formula (Ia):
(S) or (L) -enantiomer as represented by the structural formula (Ib):
(R) or (D) -enantiomer as represented by

Rx, R ₁ and R ₂ are all selected from hydrogen and x is preferably 1. Such a compound is represented by the following formula.

  Embodiments of the present invention provide a method of using an enantiomer of formula (I) that is an enantiomer of formula (Ib), or an enantiomeric mixture that is predominantly enantiomer of formula (Ib), substantially free of other enantiomers. Including. (Note: In the structural formula of formula (Ib) located on the lower side, the amino group bonded to the β carbon protrudes to the back side of the paper. This compound is a dextrorotatory compound whose absolute configuration is (R). (D) Enantiomer.)

  The abused drug is selected from the group consisting of nicotine, cocaine, opioid, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA), and other addictive substances.

  These and other objects of the present invention will be more fully understood from the following description of the invention and the appended claims.

The present invention includes, as an active ingredient, a compound having the structural formula (I), an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a hydrate, solvate, pharmaceutically acceptable salt thereof, A pharmaceutical composition for treating drug addiction comprising an ester or an amide; a therapeutically effective amount of a compound having structural formula (I), an enantiomer, diastereomer, racemate, or a mixture thereof, or A method of treating drug addiction comprising administering a hydrate, solvate, pharmaceutically acceptable salt, ester, or amide to a mammal in need of treatment:
Wherein R is hydrogen; lower alkyl having 1 to 8 carbon atoms; halogen selected from F, Cl, Br, and I; alkoxy having 1 to 3 carbon atoms; nitro group; hydroxy; trifluoromethyl And selected from the group consisting of thioalkoxy having 1 to 3 carbon atoms;
x is an integer from 1 to 3, but when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different and are each selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, and cycloalkyl having 3 to 7 carbon atoms;
R ₁ and R ₂ may combine to form a 5- to 7-membered heterocyclic ring substituted with a substituent selected from the group consisting of hydrogen, an alkyl group, and an aryl group. 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, which are not directly bonded to each other or to the oxygen atoms).

In addition, the method of the present invention can be used to produce a compound of formula (Ia) or (Ib), or an enantiomer, diastereomer, racemate, or mixture thereof, or a hydrate, solvate, or pharmaceutically acceptable salt thereof. Including the use of a compound selected from the group consisting of:
(Wherein Rx, R ₁ and R ₂ are the same as defined above).

  Furthermore, the compositions or methods of the present invention preferably comprise the use of a D (dextrorotatory) enantiomer (of absolute configuration (R)) selected from the group consisting of formula (I) and enantiomeric mixtures thereof. In the structural formula of the formula (Ib), the amino group bonded to the β carbon protrudes to the back side of the page. This compound is a dextrorotatory (D) enantiomer having the absolute configuration (R).

As represented by the following structural formula, in the structural formula (I), Rx, R ₁ and R ₂ are preferably hydrogen and x is preferably 1.

  O-carbamoyl- (D) -phenylalaninol is also referred to as (R)-(β-amino-benzenepropyl) carbamate monohydrochloride. In the enantiomeric mixture, O-carbamoyl- (D) -phenylalaninol preferably accounts for more than about 90% of the total, more preferably about 98% or more.

  Compounds of formula (I) can be synthesized by methods known to those skilled in the art in the art. Synthetic reaction schemes for compounds of formula (I) are described in US Pat. No. 5,705,640, US Pat. No. 5,756,817, US Pat. No. 5,955,499, and US Pat. No. 6,140,532. Details of the above reaction scheme and representative examples in the preparation of specific compounds are also described in US Pat. No. 5,705,640, US Pat. No. 5,756,817, US Pat. No. 5,955,499, US Pat. No. 6,140,532, Are all incorporated herein by reference in their entirety.

  Salts and esters of compounds of formula (I) can be prepared by acid (HX) treatment of the compounds in a suitable solvent or methods well known to those skilled in the art.

  From structural formula (I) it is clear that some of the compounds of the present invention have at least one or possibly more asymmetric carbon atoms. The present invention is intended to include within its scope stereochemically pure isomers of the compounds of structural formula (I) and their racemates. Stereochemically pure isomers may be obtained by applying principles known in the art. Diastereomers may be separated by physical separation methods such as fractional crystallization, chromatographic methods, etc. Enantiomers may be selectively crystallized by diastereomeric salts using optically active acids or bases, or chiral It may be separated by chromatography. Pure stereoisomers may also be prepared synthetically by using appropriate and stereochemically pure starting materials, or by using stereoselective reactions.

  In any process of preparing the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on the molecule. Such protection is as described in Protective Groups in Organic Chemistry, edited by JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. It may be achieved by a method using a conventional protecting group. The protecting groups may be removed at a convenient subsequent step using methods known in the art.

  The present invention is based in part on the discovery that the phenylalkylaminocarbamate of formula (I) described above has novel and unique pharmacological properties. In a number of animal models, these compounds have been shown to have the effect of treating abuse drug addiction and behavioral changes associated with abuse drug addiction.

  Although the exact mechanism of action is not fully understood, it is known that the compounds of the invention differ in mechanism of action from most other known therapies used for abuse drug addiction. For these reasons, the compounds of formula (I) are particularly suitable for use as monotherapy or adjunct therapy for abused drug addiction and behavioral changes associated with abused drug addiction.

  Therefore, these compounds can be used safely either alone or in combination with other useful drugs, but when used in combination, the effects are enhanced and the dose of each drug is reduced, reducing side effects. The

  In one aspect, the invention provides a therapeutically effective amount of one or more carbamate compounds of the invention, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, diluent, or excipient as an active ingredient. And a use of the composition for treating a subject suffering from abused drug addiction, and a therapeutically effective amount of one or more carbamate compounds of the invention, or a pharmaceutically acceptable salt or ester thereof And a pharmaceutically acceptable carrier, diluent, or excipient to the subject, and a method of treating a subject suffering from abused drug addiction.

  In one aspect, the invention further comprises a composition comprising an effective amount of a carbamate compound of the invention as an active ingredient for reducing, inhibiting, or eliminating the reward / incentive effect of an abused drug in a subject suffering from drug addiction, and Use of the composition; and the administration of an abused drug in a subject suffering from drug addiction comprising administering to the subject an effective amount of a carbamate compound of the invention to reduce, inhibit, or eliminate the reward / incentive effect of the abused drug Provide a way to reduce, inhibit or eliminate reward / incentive effects.

  The abused drug is selected from the group consisting of nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA), and other addictive substances.

Definitions of Terms For convenience, certain terms used in the specification, examples, and appended claims are collected below.

  It is to be understood that the present invention is not limited to the particular methodologies, protocols, animal species, and reagents described herein, which can be varied. Moreover, the terminology used herein is for the purpose of describing particular embodiments only, and these terms limit the scope of the invention which is limited only by the appended claims. It is also understood that is not intended.

  As used herein, “subject” refers to an animal, preferably a mammal, and most preferably a human sex, that is the subject of treatment, observation or experiment.

  As used herein, “therapeutically effective amount” refers to one or more signs or symptoms of the disease or disorder being treated in a tissue system, animal or human being sought by a researcher, veterinarian, physician or other clinician. The amount of active compound or pharmaceutical agent that elicits a biological or medical response including relaxation is meant.

  A “prophylactically effective amount” refers to the prevention or risk of the occurrence of a biological or medical event to be prevented in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician. It is intended to mean the amount of pharmaceutical product that is to be reduced.

  “Pharmaceutically acceptable salt or ester” means a non-toxic salt or ester of a compound used in the invention, usually prepared by reacting the free acid with a suitable organic or inorganic base. . Such salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, cansylate, carbonate Salt, chloride salt, clavulanic acid, citrate, dihydrochloride, edetate, edicylate, estrate, esylate, fumarate, glucoceptate, gluconate, glutamate, glycolyl Arsanylate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide salt, isothionate, lactate, lactobionate, laurate, malic acid Salt, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, oleate, oxalate, pamoate Palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium salt, salicylate, sodium salt, stearate, basic acetate, succinate, tannate, tartrate, These include, but are not limited to, teocrate, tosylate, triethiozide, and valerate.

  Thus, as used herein, a “patient in need of treatment” refers to any subject or patient who currently has or is likely to develop the above syndrome or disorder, including any mood disorder treatable with an antidepressant; Others in which administration of one or more compounds of formula (I) alone or in combination with another therapeutic intervention (including but not limited to another drug administration) is effective for the patient's current clinical symptoms or prognosis thereof Refers to any subject or patient who currently has or is likely to develop a disorder. “Patient” refers to, but is not limited to, humans, including human and female patients; non-human primates; laboratory animals such as rabbits, rats, mice; and any mammal including other animals.

  As used herein, “treat” or “treatment” refers to any sign of abuse drug addiction and the successful prevention or alleviation of injury, condition or condition due to behavioral changes associated with abuse drug addiction, including such signs Remission; Remission; Relief of symptoms, or the patient being able to tolerate an injury, medical condition, or condition; Delay of degeneration, debilitating or worsening of the disease; Include any objective or subjective parameters such as improving the physical and mental health of the subject. Symptom treatment or alleviation may be based on objective or subjective parameters including results of physical examination, neurological examination, and / or psychological examination. Thus, “treating” or “treatment” includes administering a compound or agent of the invention to treat any form of abused drug addiction in human men and women. In some cases, treatment with a compound of the invention is intended to be performed in combination with other compounds that prevent, inhibit, or prevent the progression of abused drug addiction.

  As used herein, “therapeutic effect” refers to effective amelioration or alleviation of symptoms of abuse drug addiction. As used herein, “therapeutically effective amount” means that one or more compounds of the present invention provide a therapeutic effect as defined above in a subject or patient in need of such neuroprotective treatment. Mean enough.

  Methods for determining therapeutically effective and prophylactically effective doses for the pharmaceutical compositions of the present invention are known in the art. For example, the compounds of the present invention can be used at an average adult human dosage of about 0.1 to 400 mg daily, usually in 1-2 dosages per day. However, the effective amount may vary depending on the particular compound used, the method of administration, the efficacy of the formulation, the method of administration, and the progression of the condition. Furthermore, it will be necessary to adjust the dose depending on factors associated with the individual patient being treated, including the age, weight, diet, and time of administration of the patient.

  The compounds of the present invention may be administered to a subject by any conventional route of administration, including intravenous administration, oral administration, subcutaneous administration, intramuscular administration, intradermal administration, and parenteral administration, It is not limited to these. Depending on the route of administration, the compound of formula (I) can be in any form. For example, forms suitable for oral administration include pills, gel capsules, tablets, caplets, capsules (all of which are immediate release formulations, timed release formulations and sustained release formulations) ), Solid forms such as granules and powders. Examples of forms suitable for oral administration further include liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. In addition, forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

  In order to prepare the pharmaceutical composition of the present invention, one or more compounds of the formula (I) or a salt thereof as an active ingredient are mixed well with a pharmaceutical carrier according to a conventional pharmaceutical compounding technique. Carriers are essential and inert pharmaceutical additives, including but not limited to binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coating agents. Any conventional pharmaceutical carrier may be used in preparing the composition for oral administration. For example, carriers and additives suitable for liquid oral formulations include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc .; as carriers and additives suitable for solid oral formulations Include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. The above carrier for parenteral use will usually contain sterile water, but may contain other ingredients, eg for the purpose of improving solubility or storage. In addition, suspensions for injection may be prepared, and in this case, appropriate liquid carriers, suspending agents and the like may be used.

  Because of their ease of administration, the most advantageous oral dosage unit forms include tablets and capsules, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Suppositories may also be prepared, in which case cocoa butter can be used as a carrier. Tablets or pills can be coated or formulated to give a dosage form that provides the benefit of sustained action. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component, wherein the outer dosage component is formed to wrap around the inner dosage component. The two components can be separated by an enteric layer, which suppresses disintegration in the stomach and prevents passage through the duodenum without delaying the inner component or delays its release. to enable. A variety of materials can be used for such enteric layers or enteric coatings, such materials include various polymeric acids including materials such as shellac, cetyl alcohol, cellulose acetate and the like.

  The above active ingredients can also be administered by liposome delivery systems such as small unilamellar liposomes, large unilamellar liposomes, and multilamellar liposomes. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  Alternatively, the active ingredient may be delivered by using a monoclonal antibody as a carrier and binding the molecule of the compound of the present invention thereto. The active ingredient may also be combined with a soluble polymer as a targetable drug carrier. Such polymers include polyvinyl pyrrolidone, pyran copolymers, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, and polyethylene oxide polylysine substituted with palmitoyl groups. Furthermore, the active ingredient may be combined with biodegradable polymers useful for controlled drug release, such as polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymer, Polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogel crosslinkable or amphiphilic block copolymers.

  The above compositions are for tablets, pills, capsules, powders, granules, sterile, non-oral, parenteral, intranasal, sublingual, rectal, or inhalation or insufflation. A unit dosage form such as an oral solution or suspension, a metered aerosol or liquid spray, a drop, an ampoule, a self-injection device, or a suppository is preferred.

  Alternatively, the composition of the present invention may be in a form suitable for weekly administration or monthly administration. For example, an insoluble salt (eg, decanoate) of an active compound of the present invention may be adapted to provide a depot preparation for intramuscular injection.

  The pharmaceutical composition of the present invention has an amount of active ingredient necessary to deliver the above effective dose per dosage unit (eg, tablet, capsule, powder, injection, teaspoon, suppository, etc.). Shall be included. For example, the pharmaceutical composition of the present invention may contain about 25-400 mg of active ingredient per dosage unit. The amount of the active ingredient is preferably about 50 to 200 mg.

  In some embodiments of the present invention, carbamate compounds suitable for use in the practice of the present invention are those administered alone or in combination with at least one or more other compounds or therapeutic agents. In these embodiments, the present invention provides methods of treating abuse drug addiction and behavioral changes associated with abuse drug addiction in a patient. The method includes the step of administering to a patient in need of treatment an effective amount of any of the carbamate compounds disclosed herein in combination with an effective amount of one or more other compounds or therapeutic agents.

  It goes without saying that a person skilled in the art can select chemically substituents and substitution patterns in the compounds of the present invention and provide chemically stable compounds that can be easily synthesized by techniques known in the art and the methods described herein. .

Representative 2-phenyl-1,2-ethanediol monocarbamates and dicarbamates include, for example, the following compounds:

  The present invention includes the use of an isolated enantiomer of formula (I). In one preferred embodiment, a pharmaceutical composition comprising an isolated S-enantiomer of formula (I) is used to treat a substance abuse addiction in a subject. In yet another preferred embodiment, a pharmaceutical composition comprising an isolated R-enantiomer of formula (I) is used to treat a substance abuse addiction in a subject.

  Furthermore, the present invention includes the use of enantiomeric mixtures of formula (I). In one embodiment of the invention, one enantiomer is said to occupy the majority. An enantiomer that occupies the majority of the mixture is an enantiomer that is present in a greater amount than any of the other enantiomers present in the mixture, and the amount is, for example, greater than 50%. In one embodiment, one enantiomer accounts for 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more. In a preferred embodiment, the enantiomer accounting for the majority of the composition comprising the compound of formula (I) is the S-enantiomer of formula (I).

  The present invention provides methods for using enantiomers and enantiomeric mixtures of the compounds of formula (I). The carbamate enantiomer of formula (I) contains an asymmetric (chiral) carbon at the benzyl position, which is the aliphatic carbon located second from the phenyl ring.

  An isolated enantiomer is substantially free of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that has been separated by separation techniques or that has been prepared so as not to include the corresponding enantiomer. As used herein, “substantially free” means that one enantiomer accounts for a very large proportion of the composition of the compound. In a preferred embodiment, the compound comprises at least about 90% by weight of the preferred enantiomer. In other embodiments of the invention, the compound comprises at least about 99% by weight of a preferred enantiomer. Preferred enantiomers can be isolated from the racemic mixture by any method known to one of ordinary skill in the art, such methods include high performance liquid chromatography (HPLC), and chiral salt generation and crystallization. . Alternatively, preferred enantiomers can be prepared by the methods described herein.

Carbamate compounds as pharmaceuticals:
The present invention provides racemic mixtures, enantiomeric mixtures, and isolated enantiomers of formula (I) as pharmaceuticals. The carbamate compound of the present invention is formulated as a pharmaceutical and provides ancillary antidepressant action to the subject.

  The carbamate compounds of the present invention can usually be administered as a pharmaceutical composition by any therapeutic agent administration method known in the art, including oral administration, buccal administration, and topical administration. , Systemic administration (eg, transdermal administration, intranasal administration, or suppository administration), and parenteral administration (eg, intramuscular administration, subcutaneous administration, or intravenous injection). As a method for directly administering the compound of the present invention to the nervous system, for example, a needle or catheter with or without a pump device is inserted into the skull or spine, and delivery is performed. Intraventricular, intrathecal, intracisternal, intraspinal, or perispinal administration.

  The composition can be in the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols, or other suitable compositions. It can comprise at least one compound of the invention in combination with at least one pharmaceutically acceptable additive. Suitable additives are well known to those skilled in the art. These additives and methods for formulating the compositions are described in standard references such as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton PA, 1985, etc. The contents are hereby incorporated by reference in their entirety for all purposes. Suitable liquid carriers, particularly those suitable for injectable solutions, include water, saline, aqueous dextrose, and glycols.

  The carbamate compounds of the invention can be provided as an aqueous suspension. The aqueous suspension of the present invention can contain a carbamate compound with additives suitable for the manufacture of the aqueous suspension. Such additives include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic; and natural phosphatides (eg lecithin), alkylene oxides Of fatty acid and fatty acid (for example, polyoxyethylene stearate), condensate of ethylene oxide and long-chain aliphatic alcohol (for example, heptadecaethyleneoxycetanol), condensation of fatty acid and partial ester derived from hexitol with ethylene oxide Products (for example, polyoxyethylene sorbitol monooleate), fatty acid, and a condensate of ethylene oxide with a partial ester derived from hexitol anhydride ( For example, dispersing or wetting agents such as monooleate polyoxyethylene sorbitan) and the like.

  The aqueous suspension further comprises one or more preservatives such as ethyl p-hydroxybenzoate, p-hydroxybenzoate-n-propyl; one or more colorants; one or more flavoring agents; and sucrose, aspartame, One or more sweeteners such as saccharin can be included. The osmolality of the formulation can also be adjusted.

  The oily suspension used in the method of the present invention is formulated by suspending the carbamate compound in vegetable oil such as peanut oil, olive oil, sesame oil, coconut oil; mineral oil such as liquid paraffin; or a mixture thereof. be able to. Oily suspensions may contain thickening agents such as beeswax, hard paraffin, cetyl alcohol and the like. Sweetening agents such as glycerol, sorbitol and sucrose can be added to provide a palatable oral preparation. Such a preparation can be preserved by adding an antioxidant such as ascorbic acid. For injectable oily vehicles, see Minto, J. Pharmacol. Exp. Ther. 281: 93-102, 1997. Furthermore, the pharmaceutical formulation of the present invention can be in the form of an oil-in-water emulsion. The oily phase of the emulsion may be a vegetable oil, a mineral oil or a mixture thereof as described above.

  Suitable emulsifiers include natural gums such as gum arabic and tragacanth; natural phosphatides such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate; and polyoxy monooleate The condensate of the said partial ester and ethylene oxide, such as ethylene sorbitan, is mentioned. The emulsion can further contain sweetening and flavoring agents, such as syrups and elixirs. Such formulations can further contain a demulcent, a preservative, or a coloring agent.

  Selected compounds, alone or in combination with other suitable ingredients, can be aerosolized for administration by inhalation (ie, can be “nebulized”). The aerosol can be in an acceptable pressurized propellant such as dichlorodifluoromethane, propane, nitrogen.

  Suitable formulations for parenteral administration, such as intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous or non-aqueous sterile isotonic injections, And aqueous or non-aqueous sterile suspensions. The injection solution may contain an antioxidant; a buffer; a bacteriostatic agent; and a solute that makes the formulation isotonic with the blood of the intended recipient. The suspension may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic saline. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterilized and are usually free of undesirable substances.

  When the compound of the present invention has sufficient solubility, it can be directly dissolved in normal physiological saline with or without the use of an appropriate organic solvent such as propylene glycol or polyethylene glycol. The micronized compound can be prepared as a dispersion using a suitable oil such as aqueous starch or sodium carboxymethylcellulose solution, or peanut oil. Such a preparation can be sterilized by a conventionally known sterilization technique. Such formulations may contain pharmaceutically acceptable adjuvants such as pH adjusters, buffers, isotonic agents, and the like that are needed to approximate physiological conditions. Examples thereof include sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

  The concentration of the carbamate compound in the formulation can vary widely and is selected primarily based on fluid volume, viscosity, patient weight, etc., according to the particular method of administration selected and the needs of the patient. For intravenous administration, the formulation can be a sterile injectable formulation, such as an aqueous or oily sterile injectable suspension. Such suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents and suspending agents. Furthermore, the sterile injectable preparation can be made into a sterile injectable solution or suspension using a non-orally acceptable non-toxic diluent or solvent such as a 1,3-butanediol solution. The recommended formulation may be in unit dose form or multiple dose form provided in a closed container such as an ampoule or vial. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets, as described above.

  Carbamate compounds suitable for use in the practice of the present invention can be administered orally and this route of administration is preferred. The amount of the compound of the invention in the composition can vary widely depending on the type of composition, the size of the unit dosage form, the type of additive, and other factors well known to those skilled in the art. Usually, the final composition can contain, for example, 0.000001 to 50% by weight, preferably 0.00001 to 25% by weight, of the carbamate compound, the remainder being occupied by one or more additives.

  A pharmaceutical preparation for oral administration can be formulated using a pharmaceutically acceptable carrier well known in the art to obtain a dose suitable for oral administration. The pharmaceutical preparation is a unit dosage suitable for ingestion by patients such as tablets, pills, powders, dragees, capsules, solutions, lozenges, gels, syrups, slurries, suspensions, etc. It can be formulated into a form.

Formulations suitable for oral administration are
(A) a solution such as an effective amount of a pharmaceutical preparation suspended in a diluent such as water, physiological saline or PEG400;
(B) capsules, sachets or tablets containing a predetermined amount of an active ingredient as a liquid, solid, granule or gelatin;
(C) a suspension using a suitable liquid; and (d) a suitable emulsion.

  Pharmaceutical preparations for oral administration can be obtained by combining the compounds of the present invention with solid additives, and if necessary, the resulting mixture may be ground and after adding the appropriate additional compounds If desired, the granular mixture can be made into tablets or dragee cores. Suitable solid additives are carbohydrate or protein derived fillers, such as sugars including lactose, sucrose, mannitol, and sorbitol; derived from corn, wheat, rice, potato, or other plants Starches such as methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; gums such as gum arabic and tragacanth; and proteins such as gelatin and collagen.

  If desired, disintegrating or solubilizing agents can be added, examples include cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof such as sodium alginate. Tablets include lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, crystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, other excipients, colorants, fillers, One or more of a binder, diluent, buffer, wetting agent, preservative, flavoring agent, dye, disintegrant, and pharmaceutically acceptable carrier can be included. The lozenge may contain an active ingredient together with a flavoring agent such as sucrose. Similarly, pastilles may contain the active ingredient together with an inert base such as gelatin, glycerin, sucrose, gum arabic and the like. Emulsions, gels and the like may contain carriers known in the art in addition to the active ingredients.

  The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. Such formulations can be prepared by mixing the drug with an appropriate nonirritating additive that is solid at room temperature but liquid at the rectal temperature so it can dissolve in the rectum and release the drug. it can. Such materials include cocoa butter and polyethylene glycol.

  The compounds of the present invention can also be administered by nasal route, intraocular route, intravaginal route, rectal route as suppositories, inhalants, powders, aerosol formulations and the like (for example, as steroid inhalants, Rohatagi J. Clin. Pharmacol. 35: 1187-1193, 1995; and Tjwa, Ann. Allergy Asthma Immunol. 75: 107-111, 1995).

  The compounds of the present invention can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, coatings, powders, or aerosols by the topical route It can be delivered transdermally.

  Encapsulating materials can also be used with the compounds of the present invention. “Composition” also includes active ingredients in combination with encapsulating materials as a formulation, with or without other carriers. For example, the compounds of the present invention can be delivered as sustained release microspheres in the body. In one embodiment, the administration of the microspheres is a subcutaneous sustained release microsphere for intradermal injection containing a drug (eg, mifepristone) (Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); microspheres as biodegradable gels for injection (see, eg, Gao, Pharm. Res. 12: 857-863, 1995); or microspheres for oral administration (eg, Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). Both transdermal and intradermal routes deliver a certain amount of drug over weeks or months. Cachets can also be used to deliver the compounds of the present invention.

  In yet another embodiment, the endocytosis is ultimately achieved by using liposomes that are fused or endocytosed to the cellular membrane, ie, by attaching a ligand that binds to the cell's membrane surface protein receptor to the liposome. Tosis occurs and the compounds of the invention can be delivered. Concentrated delivery of carbamate compounds to target cells in vivo by using liposomes, particularly liposomes having a ligand specific to the target cell on the surface, or liposomes that target a specific organ by another method (Eg, Al-Muhammed, J. Microencapsul. 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6: 698-708, 1995; and Ostro, Am. J. Hosp. Pharm. 46 : 1576-1587, 1989).

  The pharmaceutical formulations of the present invention can be provided as salts, which can be formed using various acids. Examples of the acid include, but are not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be soluble in aqueous or other protic solvents, which are the corresponding free base forms. In other cases, a preferred formulation of the present invention may be a lyophilized powder, which has a pH upon dissolution of, for example, 4.5-5.5, 1-50 mM histidine, 0. Any or all of 1-2% sucrose and 2-7% mannitol may be included and the lyophilized powder is combined with a buffer prior to use.

  Pharmaceutically acceptable salts and esters refer to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include those that may be formed by reacting acidic protons present in the compounds of the invention with inorganic or organic bases. Suitable inorganic salts include salts formed with alkali metals (eg, sodium, potassium, magnesium, calcium, aluminum, etc.). Suitable organic salts include salts formed with organic bases such as amine bases (eg, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). Pharmaceutically acceptable salts further include amine moieties in the parent compound and inorganic acids (eg, hydrochloric acid and hydrobromic acid) and organic acids (eg, acetic acid, citric acid, maleic acid, and methanesulfonic acid and And acid addition salts formed from the reaction with alkane sulfonic acids such as benzene sulfonic acid and arene sulfonic acids). Pharmaceutically acceptable esters include esters formed from carboxy groups, sulfonyloxy groups, and phosphonoxy groups present in the compounds of the present invention. Where two acidic groups are present, the pharmaceutically acceptable salt or ester may be a monoacid-monosalt or monoacid-monoester, or a disalt or diester; If the number of is greater than 2, some or all of such groups may be salified or esterified.

  The compounds described in the present invention can exist in non-chlorinated or non-esterified forms, in chlorinated and / or esterified forms, the name of such compounds being the original (non-chlorinated or non-esterified) compounds Is also intended to include pharmaceutically acceptable salts and esters thereof. The present invention includes pharmaceutically acceptable salts and esters of formula (I). Two or more enantiomeric crystals of formula (I) may be present and such are also included in the present invention.

  In addition to the carbamate compound, the pharmaceutical composition of the present invention may comprise at least one other therapeutic agent useful for the treatment of abused drug addiction. For example, to simplify administration, the carbamate compound of formula (I) can be physically combined with other addiction treatments as a multidrug mixture.

  Methods for formulating pharmaceutical compositions are published by Marcel Dekker, Inc., Pharmaceutical Dosage Forms: Tablets.Second Edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems. It has been described in numerous publications, including Volumes 1-2, edited by Lieberman et al. For this purpose is hereby incorporated by reference in its entirety.

  The pharmaceutical composition of the present invention is usually formulated as a substantially isotonic sterile formulation in full compliance with the US Food and Drug Administration's Standards for Manufacturing Control and Quality Control (GMP).

Usage The present invention provides a method of providing a supplementary antidepressant effect to a mammal by using a carbamate compound. The amount of carbamate compound required to reduce or treat abused drug addiction is defined as a therapeutically effective dose or a pharmaceutically effective dose. The dosage regimen and the effective doses used therein, i.e., dosage and usage, will depend on various factors including disease stage, patient physical condition, patient age and the like. When determining patient use, the method of administration is also taken into account.

  One of ordinary skill in the art, without undue experimentation, will determine a therapeutically effective amount of an individual substituted carbamate compound to practice the present invention, taking into account its own technology and the disclosure herein. (See, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The art, Science and Technology of Pharmaceutical Compounding; and Pickar, 1999, Dosage Calculations). The therapeutically effective dose is also an amount that provides a therapeutically beneficial effect clinically over any toxic or harmful side effects of the active ingredient. Furthermore, specific usage in individual subjects will be evaluated and adjusted over time, depending on the needs of each patient and the professional judgment of the person administering or supervising the administration of the compound of the invention. Also note that it should.

  For therapeutic purposes, the compositions or compounds disclosed herein may be administered as a single bolus, continuous over a prolonged period, or a repeated dose protocol (eg, hourly, daily, or weekly). Can be administered to the subject. The pharmaceutical formulations of the present invention can be administered, for example, once or more daily, three times a week, or weekly. In one embodiment of the invention, the pharmaceutical formulation of the invention is administered orally once or twice daily.

  As used herein, a therapeutically effective dose of a carbamate compound can include repeated doses that would produce clinically significant results for treating abused drug addiction in a long-term treatment regime. Effective doses herein are usually effective doses that significantly reduce the occurrence of, or the severity of, a targeted exposure symptom or condition in a subject, based on studies in animal models and subsequent clinical trials in humans. It is determined by defining the administration protocol. Suitable models in this case include, for example, murine animals, rats, pigs, cats, non-human primates, and other generally accepted animal models known in the art. Alternatively, an effective dose can be determined using in vitro models (eg, immunological analysis and histopathological analysis). Using such a model, usually with general calculations and adjustments, the appropriate concentration and dosage for administering a therapeutically effective amount of the bioactive agent (eg, to elicit the desired response) Effective nasal doses, transdermal doses, intravenous doses, or intramuscular doses) can be determined.

  In an exemplary embodiment of the invention, the unit dosage form of the compound is prepared for a standard dosage regimen. In this way, the composition of the present invention can be easily subdivided into low doses as directed by a physician. For example, the unit dose can be in the form of individually packaged powders, vials, or ampoules, preferably in the form of capsules or tablets.

  The amount of active compound contained in unit dosage forms of the compositions of the invention can be about 10 mg to 1 g or more in one or more daily administrations, eg, depending on the individual needs of the patient. . By starting a treatment regimen with a minimum daily dose of about 1 g, it is possible to determine whether to increase or decrease the dose depending on the blood concentration of the carbamate compound.

  The carbamate compound of the present invention can be effectively administered, for example, at an oral dose or parenteral dose of about 0.01 to 150 mg / kg / dose. The above dose is preferably about 0.1 to 25 mg / kg / dose, more preferably about 0.2 to 18 mg / kg / dose. Thus, the therapeutically effective amount of active ingredient contained per dosage unit described herein may be, for example, about 1-7000 mg / day for a subject having an average body weight of, for example, 70 kg.

  The methods of the present invention further provide kits that are used to provide treatment for abused drug addiction. In order to provide treatment for substance abuse addiction, a pharmaceutical composition comprising one or more carbamate compounds of the invention is optionally formulated with one or more other therapeutically beneficial compounds and formulated with a suitable carrier After that, the label may be put in an appropriate container. Furthermore, for the treatment of the above-mentioned diseases, another pharmaceutical agent containing at least one other therapeutic agent useful for the treatment of drug abuse addiction may be similarly placed in a container and labeled. Such label display may include, for example, a description of the dosage, administration frequency, and administration method of each pharmaceutical product.

  Although the foregoing invention has been described in detail by way of example for clarity of understanding, it is intended that the disclosure of the invention include certain changes and modifications and be limited without undue experimentation. It will be apparent to those skilled in the art that these changes and modifications can be made within the scope of the appended claims described without reference. The following examples are presented to illustrate specific embodiments of the invention and are not intended to limit the invention in any way.

  The invention will be better understood in light of the following examples which are set forth to illustrate the invention and are not to be considered as limiting the invention in any way.

Example 1
The test compound (O-carbamoyl- (D) -phenylalaninol) was a complete replacement for the discriminative stimulating effect produced by 10 mg / kg cocaine (ED50 = 37.43 mg / kg). The response rate decreased to 41% of the control after administration of 100 mg / kg of the test compound.

(Method)
It was evaluated using rats whether or not the test compound can replace the discrimination stimulating effect of cocaine (10 mg / kg).

  Using the two-lever selection method, six Sprague-Dawley male rats were trained to discriminate between cocaine (10 mg / kg) and saline. When a response was indicated by a lever corresponding to each injection, the diet was made available as a fortifier under a constant ratio (FR10) schedule. All experiments were performed in standard commercial chambers (Coulbourne Instruments) using 45 mg diet pellets (Bioserver) as a fortifier.

  The training session is carried out with two alternating training sessions, and the experiment is performed between two identical training sessions and two identical training sessions (ie, two saline or cocaine training sessions). Between two saline or cocaine training sessions). A baseline of 85% of subjects who responded spontaneously with the correct injection lever in both the primary reinforcer (primary constant ratio) and the entire session in the two previous training sessions The experiment was conducted only when The experimental session lasted 20 minutes or until 20 reinforcements were given. If less than 3 rats were able to complete the primary fixed ratio, the test compound dose was considered to have failed to exert a discriminative stimulus effect.

  Test compound (1 ml / kg) or its vehicle (0.9% saline) was injected intraperitoneally 60 minutes before the start of the experimental session. The starting dose of test compound, 2.5 mg / kg, was determined based on data provided by the investigator. The evaluated dose was 2.5 to 100 mg / kg. This dosage range includes doses that do not exhibit activity to doses that exert the biological activity shown to be a complete replacement.

(result)
Whole session The test compound was a complete replacement for the discriminative stimulating effect produced by 10 mg / kg cocaine. The ED50 value of 37.43 mg / kg was determined by linear regression of the logarithm (log 10) of the dose of 10 to 100 mg / kg. The response rate decreased to 41% of the vehicle control after administration of 100 mg / kg of the test compound. A one-factor repeated measures analysis of variance was performed on the response rate for the entire session (in 4 rats receiving the total dose) to find a significant overall effect (F (6,18) = 3.38, p. = .021); a planned comparison to the vehicle control (a priori contrast) showed a significant difference at a dose of 100 mg / kg (in FIG. 1, all cases where p <0.05) (Indicated by an asterisk).

Primary Reinforcer The measurement results for the primary reinforcer were almost consistent with the data for the entire session. The ED50 value of 37.45 mg / kg was determined by linear regression of the logarithm (log 10) of the dose of 10 to 100 mg / kg. The response rate decreased to 37% of the vehicle control after administration of 100 mg / kg of the test compound. A one-factor repeated measures analysis of variance was performed on the response rate of primary reinforcers (in 4 rats ingesting the full dose) to find a significant overall effect (F (6,18) = 3.82). P = .012); a planned comparison (a priori contrast) to vehicle control showed a significant difference at a dose of 100 mg / kg.

Example 2
Whether or not test compound (O-carbamoyl- (D) -phenylalaninol) (0.1-18 mg / kg) can replace cocaine was determined by drug discrimination method using cocaine (0.40 mg / kg) and physiological saline. Were evaluated using 4 monkeys trained to discriminate between. In all four monkeys, the test compound was a complete replacement for cocaine in a dose-dependent manner. Over the entire dose range evaluated, administration of the test compound increased the response rate in 2 monkeys, and cocaine also increased the response rate in these 2 monkeys. In the third monkey, the response rate did not change with either the test compound or cocaine, and in the fourth monkey, the response rate decreased with either the test compound or cocaine. Furthermore, the test compound did not produce a clear behavioral effect over the entire dose range evaluated. These results suggested that the test compound has a behavioral effect on rhesus monkeys similar to cocaine, but its potency is about one-twentieth that of cocaine.

(Method)
Subject:
Subjects were four male rhesus monkeys (Macaca mulatta) weighing 7.0-8.0 kg. Each of these monkeys was fed with a diet consisting of 7 to 12 monkey biscuits (Purina Monkey Chow Jumbo # 5037) and one fresh fruit per day. On weekdays, we were fed after the experimental session, but on weekends we were fed between 9 am and noon. Water was always available freely. The room containing the monkeys was lit from 7 am to 7 pm and was managed with a 12 hour light / dark cycle.

  Throughout the experiment, these monkeys were able to contact each other visually, audibly and olfactoryly. Operant diet self-administration provides opportunities for environmental adjustment and environmental improvement.

apparatus:
Each monkey was individually housed in a well-ventilated stainless steel chamber (56 x 71 x 69 cm). All monkey housing cages were modified and operant panels (28 x 28 cm) were installed on the front wall. Three translucent and square reaction keys (6.4 × 6.4 cm) were placed side by side at an interval of 2.54 cm at a location 3.2 cm from the top of the operant panel. Each key was able to transmit red or green stimulation light (Superbright LED'S). In addition, outside the operant panel, 1 g of fruit-flavored food pellets (Precision Primates Formats L / I Banana Flavor, PJ Noies Co., Lancaster, NH) was placed at the bottom of the operant reaction panel in the cage. A pellet dispenser (Gerbrands, model G5310, Arlington, MA) was installed to feed the food container. Operant panel operation and data collection were performed with an IBM compatible computer and interface system (Med Associates; St Albans, VT) installed in a separate room.

Discrimination training:
In the discrimination training, a one-day session including a plurality of cycles was performed five days a week. Each cycle consisted of a 15 minute timeout followed by a 5 minute reaction period. At time-out, all stimulation light was extinguished and no response was given based on the schedule even if a response was shown. In the reaction phase, red or green light was transmitted through the left and right reaction keys so that monkeys could obtain up to 10 food pellets by responding to food presentation in the FR30 schedule. For all four monkeys used in this experiment, green light was transmitted through the left key and red light was transmitted through the right key. The central key was not lit at all, and no result was given based on the schedule, even if a response was indicated by the central key. If all available food pellets are supplied before the end of the 5-minute reaction period, the stimulating light that passes through the reaction key is turned off, and no response will be given based on the schedule even if a response is indicated in the remaining time. It was.

  During the training period, monkeys were injected intramuscularly with either saline or 0.40 mg / kg cocaine 5 minutes after the start of each timeout (ie, 10 minutes before the reaction period). When the response is shown only with the green key (saline-compatible key) after administration of physiological saline, food is given, and after administration of cocaine 0.40 mg / kg, the response is shown only with the red key (drug-compatible key) If you were fed. If a response was indicated with a non-corresponding key, the FR request on the corresponding key was reset. Each session consisted of 1-5 cycles. When a cocaine training dose was administered, it was administered only in the last cycle. Thus, the training period consisted of 0-5 saline cycles followed by 0-1 drug cycles.

In each reaction phase, three dependent variables were determined using the following formula:
1) Percentage of response corresponding to injection given prior to primary reinforcement supply
2) Percentage of response corresponding to injections shown throughout the reaction phase
3) Reaction rate

In 7 of 8 consecutive training sessions, the monkey was considered to have distinguished cocaine if it met 3 of the following criteria:
1) The percentage of response corresponding to the injection shown before the primary reinforcement was over 80% in all cycles 2) The response of the response corresponding to the injection shown every cycle The percentage was over 90% in all cycles 3) Response rate in the saline training cycle exceeded 0.5 times per second

Discrimination test:
The experiment started when the monkeys met the reference level for cocaine discrimination. The experimental session was other than 1) feeding when the response was indicated by either key, and 2) administering the test compound (0.1-18 mg / kg) using an alternative protocol Was conducted in the same way as the training session. In an alternative protocol, the test compound was administered alone instead of either saline or cocaine and the dose was gradually increased. Test compounds were injected into monkeys at the start of each cycle containing multiple cycles, and each dose was increased by 1/4 or 1/2 log units.

  The experiment session was conducted only when the three criteria listed in the above “discrimination criteria” were satisfied on the training day immediately before the experiment date. The average value obtained from the physiological saline and drug cycles on the training day immediately before the first day of the experiment was used as control data on the experimental day after the training. If the response did not meet the discrimination level, training continued until the discrimination level was achieved for at least 2 consecutive days.

Data analysis:
In each subject, the percentage of response corresponding to cocaine (overall response period) and the response rate graph were plotted as a function of test compound dose (log scale). Control data for the saline and cocaine training cycles were also plotted on each graph for comparison. A test compound was considered to have been able to nearly replace cocaine if a dose corresponding to the test compound caused at least 90% of the response corresponding to cocaine. The dose of the test compound that caused 50% of the response to cocaine was defined as the ED50 value, which was linear in all monkeys that showed a dose-dependent response of 50% or more in response to cocaine. Calculated by interpolation.

Drug:
Cocaine hydrochloride was dissolved in sterile saline. The test compound was dissolved in distilled water.

(result)
During the training period prior to the experimental day, monkey responses are indicated only in the saline key in the saline cycle (mean value of responses corresponding to saline = 98.75 ± 1.25%), In the cocaine cycle, only the cocaine key was shown. The average response rate was 1.79 (± 0.44) and 2.58 (± 0.67) times / second in each of the saline and drug training cycles. Compared to the saline control response rate, monkey 92N012 and monkey L958 increased the response rate due to the training dose of cocaine, monkey 186F had no change in response rate, and monkey 153F had a response rate decreased.

  In all four monkeys, the test compound (0.1-18 mg / kg) was a complete replacement for the cocaine training stimulus. Administration of the test compound as an alternative to cocaine for all four monkeys resulted in a similar change in response rate caused by the training dose of cocaine. Specifically, due to the test compound, the reaction rate increased in monkey 92N012, the reaction rate did not change in monkey 186F, and the reaction rate decreased in monkey 153F. Over the entire dose range evaluated, the test compound caused no significant and obvious behavioral effects in any monkey.

  These results suggest that the test compound has a behavioral effect on rhesus monkeys similar to cocaine, but its potency is about one-twentieth that of cocaine.

Example 3
It was evaluated whether the test compound (O-carbamoyl- (D) -phenylalaninol) had an effect on rhesus monkey cocaine self-administration. Rhesus monkeys were trained to self-ingest cocaine (0.032 mg / kg / intravenous injection) and 1 g of banana-flavored food pellets in a 2-hour experimental session with a rapid assessment method. Each session consisted of four 20-minute drug-inoculated components and a 5-minute timeout separating each component (100 minutes). A 9-minute ingestible component was provided before and after the four drug-inoculated components. During training, changing the unit dose of cocaine for each component of the session (0.001-0.03 mg / kg / injection or 0.01-0.32 mg / kg / injection) to complete dose in cocaine self-administration— An effect curve was created. The position and slope of the dose-effect curve varied in each monkey, but cocaine self-administration under constant rate schedule conditions showed an overall inverse U-shaped function characteristic. In some sessions, the unit dose of cocaine was fixed at the top of the dose-effect curve by intravenous self-administration (0.0032 or 0.032 mg / kg / injection) across all components of the session. When the baseline cocaine dose-effect curve and how the effect of maximum potency was achieved were stable throughout the session, the test compound experiment was started.

Dose determination test using test compounds Two cocaine self-administration experiments: (1) test compound dose determination test, and (2) effect test of single dose of test compound in cocaine dose-effect curve To evaluate pretreatment with the test compound. In the first dose determination test, evaluation was performed by administering 10 to 32 mg / kg of the test compound to each monkey by intramuscular injection 30 minutes before the session. From the mean value in the monkey group, administration of 18 mg / kg or 32 mg / kg test compound maintains intravenous injection of the highest potency unit dose of cocaine without continuously interrupting feeding maintenance behavior in each monkey. It has been shown to significantly reduce self-administration behavior. The low dose test compound (10 mg / kg) did not have a consistent effect on cocaine self-administration.

Acute effects of test compounds in cocaine dose-effect curves. A rapid assessment method in a single experimental session to determine whether single intramuscular administration of test compounds has an effect on various unit doses of cocaine self-administration. Was used to evaluate. From the mean value of the monkey group, cocaine self-administration behavior was reduced by pretreatment with 32 mg / kg of the test compound by intramuscular injection under conditions where a unit dose of 0.032 to 0.32 mg / kg can be inoculated intravenously. It was also shown that the response rate increased or did not change under conditions where saline or low-dose cocaine could be inoculated. In a rapid evaluation experiment, feeding maintenance behavior was interrupted in 2 monkeys but not in the other 2 monkeys, thereby reducing the average response rate before and after the cocaine self-administration session by more than 50%. did. These data indicate that test compounds may reduce intravenous self-administration of high unit dose cocaine without consistently affecting feeding maintenance behavior.

(Method)
Subjects Trained 5 male macaques (Macaca mulatta) (89B013, 96D155, 97D105, RQ2215 and 93N082) to respond to a supply of 1 g of banana pellets on a constant rate (FR) schedule with gradually increasing FR values. This training was continued until the reaction finally stabilized at FR30. A double lumen venous catheter was then surgically inserted into each monkey under aseptic conditions. The monkeys were then trained to respond to cocaine (see below). All monkeys were bred in the same breeding situation as defined in contract DA-7-8073. Each monkey was able to contact each other visually, audibly and olfactoryly, and several types of environmental improvement devices were installed in the breeding chamber.

Devices All experimental devices were identical to those used in the drug self-administration experiments described above. Summarized below. Each monkey was individually housed in a well-ventilated stainless steel chamber (64 × 64 × 79 cm). All monkey housing cages were modified to include an operant panel (28 x 28 cm) on the front wall and equipped with a reaction key capable of transmitting red or green stimulating light (LED). In addition, on the outside of the operant panel, a pellet dispenser (Gerbrands, PJ Noyes Co., Lancaster, NH) that feeds 1 g of food pellets installed at the bottom of the operant reaction panel in the cage. Model G5210) was installed. Two syringe pumps (Model B5P-IE, Braintree Scientific, Braintree, MA; or Model 980210, Harvard Apparatus, Southner) on each cage to deliver saline or drug solution through a double lumen intravenous catheter Tick, MA). Operation of the operant panel and data collection were performed in Med Associates, Inc., installed in an adjacent room. This was carried out on an IBM-compatible computer manufactured by the company. Experimental control hardware is available from Med Associates, Inc. Controlled by customization software supplied by MedState Note.

Experimental Session A schematic diagram of the rapid evaluation method is shown below. The experimental session started twice a day at 11am and 3pm. For each session, the room light was turned off, the reaction panel was turned on, and a 2-hour session was started (see the schematic diagram below). Each session consisted of 6 reaction components and a 5 minute timeout separating each component. In the first component and the final component (each feeding component), 1 g of banana-flavored food pellets could be eaten at FR30 (10 second timeout set for 5 minutes). In the second, third, fourth and fifth components (each drug component), an intravenous injection of cocaine or saline could be inoculated with FR30 (set a 10 second timeout for 20 minutes) . The response key was lit red for the feeding component and green for the drug component. The reaction key was lit in yellow every time out for 10 seconds after the reinforcement was supplied. In the timeout between components, all lights were turned off and no response was given even if a response was shown. Prior to the 20-minute drug self-administration component, a single “priming” injection of a dose of cocaine or saline that can be inoculated in a subsequent experimental component is made non-concomitantly and yellow light is emitted. Illuminated for 10 seconds.

Change in the unit dose of cocaine in the drug self-administration component The unit dose of cocaine that can be self-administered is constant in the component of the session where the maximum effective intravenous dose of cocaine is self-administered and In rapid assessment, it varied across components. In a rapid assessment session, the unit dose that can be inoculated in each drug component was determined from 1) the infusion time of each injection and the volume determined thereby, and 2) the drug concentration in the syringe. Depending on the injection time, the injection volume varied as follows: 32 μl in 0.32 seconds; 100 μl in 1 second; 320 μl in 3.2 seconds; and 1000 μl in 10 seconds. The actual unit dose with each infusion time / infusion volume was dependent on the cocaine concentration in the syringe. For example, using cocaine at a concentration of 0.032 mg / kg / 100 μl for cocaine injection results in the following unit doses: 0.01 mg / kg in 32 μl; 0.032 mg / kg in 100 μl; 0.10 mg in 320 μl / Kg; and 0.32 mg / kg in 1000 μl. In each component of one experimental session, the cocaine dose was always increased incrementally when changing the unit dose of inoculated cocaine. In addition, the dose range evaluated at each session was varied so that overlapping cocaine dose-effect curves could be determined. For example, 0.001, 0.0032, 0.01, and 0.032 mg / kg / injection of cocaine evaluated at four drug components in one session, 0.01, 0.032, 0.10, And 0.32 mg / kg / injection cocaine may be evaluated in four components in separate experimental sessions.

Training Procedure and Training Duration Rapid assessment training began with a session consisting of only two feeding components. In the drug component, all lights were turned off and the subject was effectively transferred to timeout. Initial training continued until the response to the food pellet was reliably maintained on the FR30 schedule (FR10 for 93N082). After the feeding maintenance behavior stabilized, the drug component was added to the session and cocaine self-administration training was started. All subjects were trained to respond to cocaine with the FR30 response schedule used in the feeding maintenance behavior (FR10 response schedule for 93N082). Subsequent training included the following steps:

  (1) Initially, all monkeys were treated with 0.032 mg of cocaine without the non-concomitant “priming” injection of cocaine in the four drug components and without limiting the number of self-administerable injections in each component. Trained to self-administer / kg / injection. In addition, elimination training was initiated throughout the session by using saline instead of cocaine. Substitution with physiological saline was introduced under conditions where the training was changed every two times (ie, two sessions of cocaine self-administration were performed followed by two sessions in which physiological saline could be inoculated). When elimination of the water inoculation maintenance reaction was not sufficiently observed, the frequency of replacement with physiological saline was further increased.

  (2) After confirming that it was erased reliably, the training procedure was changed to incorporate non-concomitant priming injections at the beginning of each drug component. Initially, at the start of each component inoculated with cocaine, a priming injection of 0.032 mg / kg cocaine was given, and at the beginning of each component inoculated with saline, a priming injection of 100 μl of saline was given. Overall, the elimination behavior was hardly disturbed by the introduction of priming injections.

  (3) Several weeks after the priming injection, the training procedure was further modified to introduce various unit doses of cocaine in the self-administration component of the session. In some sessions, the syringe was filled with a cocaine solution prepared to deliver 0.032 mg / kg / injection of cocaine, and 0.01, 0.032,. The pump drive time and infusion volume were changed (high dose) so that 1 and 0.32 mg / kg injection could be delivered. In other sessions, the syringe was filled with a cocaine solution prepared to deliver 0.0032 mg / kg / injection of cocaine, and 0.001, 0.0032, 0.01 in a continuous component of one session. , And 0.032 mg / kg / injection injections were pumped and the infusion volume was changed (low dose). In the saline erasing session, saline was filled into the syringe and saline (32-11000 μl) with increasing volume was supplied for each successive component of one session.

  At the same time that cocaine administration with varying doses is introduced into the training, the dose of non-concomitant priming injection is not a constant supply (0.032 mg / kg), and is a self-administrable unit in the component immediately after training The dose was changed to be the same. After making these changes, the training was continued according to the schedule shown below without further changes.

  Experiments with test compounds were performed by administering the selected dose intramuscularly 30 minutes before the experimental session. If the data in the previous session was equivalent to the control value in cocaine self-administration and saline elimination, the experimental session was usually conducted on Tuesday or Friday. If the data in the session immediately prior to the scheduled experimental session is significantly different from the control value in cocaine self-administration or saline elimination (ie 50% response rate or number of inoculations in one or more control doses of cocaine) The test compound evaluation was postponed until a consistent value was obtained again.

Data analysis The main dependent variables in these experiments were the number of fortifiers (food pellets or injections) supplied in each component of the experimental session, and the response rate (number of key press reactions per second). The response rate was calculated by dividing the number of reactions in the session components by the component time (seconds) excluding the 10 second timeout after each feed. Because the monkey response was analyzed under a fixed rate schedule, the timeout after giving the enhancer was short (10 seconds), and the number of enhancers per component after training was not limited, The number of strengtheners per component in each monkey correlated very closely with the response rate.

Drug Cocaine hydrochloride and the test compound were dissolved in sterile saline. Cocaine is capable of intravenous self-administration and test compounds were injected intramuscularly 30 minutes before the start of the session.

(result)
Dose determination test with test compound Self-administration of cocaine If the maximum potency unit dose of cocaine (0.0032 or 0.032 mg / kg / injection) could be self-administered by intravenous injection, before test compound session Administration had an effect on the response, which varied depending on the pretreatment dose by intramuscular injection. On average, the monkey group had little effect with the pre-treatment administration of the lowest and medium doses of the test compound, but the pre-treatment administration of the maximum dose (32 mg / kg) of the test compound gave the maximum potency unit dose of cocaine. Iv self-administration of about 50%. Considering the average data, the lowest dose (10 mg / kg) of the test compound was unable to alter the cocaine intravenous self-administration behavior in any of the four monkeys, and the medium dose (18 mg / kg) With pretreatment administration of test compound, only one monkey (89B013) reduced venous self-administration of the maximum potency unit dose of cocaine by approximately 50%. In the other three monkeys, there was no change in intravenous self-administration behavior with the medium dose test compound.

  However, pretreatment administration of the maximum dose (32 mg / kg) of the test compound in each of the three experimental monkeys resulted in a 50% or more reduction in intravenous self-administration of the maximum potency unit dose of cocaine.

Feeding maintenance behavior On average in the monkey group, pretreatment administration of the test compound did not have a consistent effect on feeding maintenance behavior in the dose determination study. At the lowest dose (10 mg / kg) test compound, 2 of 4 monkeys (96D155 and 93N082) had reduced feeding maintenance response only in the component after cocaine intravenous self-administration (feeding 2) However, in the other two monkeys (89B013 and RQ2215), feeding maintenance behavior before and after intravenous self-administration of cocaine (feeding 1 and feeding 2) did not change. Even with pretreatment administration of a test compound at a medium dose (18 mg / kg), two monkeys (89B013 and 93N082) have significantly reduced feeding maintenance behavior in the component after cocaine intravenous self-administration (feeding 2) However, in the other two monkeys (96D155 and RQ2215), feeding maintenance behavior in feeding 2 did not change. In any monkey, 18 mg / kg of the test compound had little effect on the feeding maintenance behavior in the component (feeding 1) before cocaine intravenous self-administration. Pretreatment with the maximum dose (32 mg / kg) of test compound significantly reduced feeding maintenance behavior before and after the cocaine intravenous self-administration component (Fed 1 and Fed 2) in one monkey (93N082) In the other two monkeys (96D155 and RQ2215), the response did not change in any of the feeding components.

Effect of test compound (O-carbamoyl- (D) -phenylalaninol) on cocaine self-administration [rapid dose-effect method]
Cocaine Dose-Effect Data Based on the results of the above dose determination study, we will investigate how pretreatment with 32 mg / kg intramuscular injection of test compound affects various unit doses of cocaine intravenous self-administration The test compounds were further evaluated. Monkey 89B013 lost its catheter patency before the experiment and was replaced with monkey 97D105. Effect of test compound on self-administration of high unit dose (0.032-0.32 mg / kg / injection) and saline or low unit dose cocaine (0.001-0.01 mg / kg / injection) The effect of the test compound in the situation where it can be inoculated was qualitatively different. On average in the monkey group, administration of the test compound increased the response in components inoculated with saline and components inoculated with low unit doses (0.001-0.01 mg / kg) of cocaine intravenously. On the other hand, administration of the test compound reduced self-administration behavior in components in which high unit doses (0.032-0.32 mg / kg) of cocaine were inoculated intravenously.

  Average data consistently showed the effect of the test compound in 3 out of 4 monkeys (96D155, 93N082 and 97D105). In these subjects, 32 mg / kg of the test compound responded in components that could be inoculated with either saline or a low unit dose (0.001-0.01 mg / kg) of cocaine by intravenous self-administration. In components where high unit dose cocaine can be inoculated, intravenous self-administration behavior decreased in the descending portion of the inverted U-shaped dose-response curve. In the fourth monkey (RQ2215), the effect of pretreatment with the test compound 32 mg / kg was not as pronounced. The response in components inoculated with high unit doses (0.1 and 0.32 mg / kg) cocaine did not change, contradictingly, saline or unit doses were 0.001-0.032 mg Responses in components inoculated with intravenously injected cocaine in the range of / kg / injection increased.

Feeding-maintenance behavior In the monkey group, on average, the test compound 32 mg / kg fed-maintaining response in both the ingestion 1 and ingestion 2 components in the rapid assessment of the dose-response curve of cocaine intravenous self-administration Decreased significantly (over 50%). The averaged results showed that 3 out of 4 subjects had decreased feeding maintenance responses before and after intravenous cocaine administration (Feed 1 and Feed 2 components). Thus, monkey RQ2215 before cocaine intravenous self-administration (feeding one component) moderately (40%) decreased the response, and monkey 93N082 and monkey 97D10 almost eliminated the response, after cocaine intravenous self-administration ( In the fed 2 component monkeys 96D155, 93N082, and 97D105, the reaction was almost eliminated.

  From the results of the dose determination test using the test compound, if the intravenous injection of the maximum potency unit dose of cocaine could be inoculated throughout the session, pretreatment by intramuscular injection with the test compound 32 mg / kg resulted in self-administration behavior. A significant decrease was shown. On average in the monkey group, feeding maintenance behavior did not change consistently with pretreatment administration of the test compound before and after the component capable of intravenous self-administration of cocaine.

  Subsequent experiments confirmed these results and, on average, increased response with the test compound (32 mg / kg) in situations where intravenous injection of saline or low to medium doses of cocaine was possible, It has been shown that intravenous self-administration of high-dose cocaine has decreased. The combination of these effects shifts the falling part of the cocaine dose-effect curve towards the upper left. Discontinuation of feeding maintenance behavior associated with the test compound exerting an effect on cocaine self-administration was more consistent among monkeys than when the dose determination test was performed. These results indicated that pretreatment by intramuscular injection with the test compound can reduce cocaine self-administration in a manner consistent with the agonist action profile.

References All references cited herein are the same as if each publication, patent, or patent application was specifically and individually stated to be incorporated by reference in its entirety for all purposes. As such, they are incorporated herein by reference in their entirety for all purposes.

  The discussion of cited references herein is merely to summarize the assertions made by the author, and no cited reference constitutes prior art. Applicant reserves the right to challenge the accuracy and appropriateness of cited documents.

  The present invention is not limited to the individual embodiments described in this application, but these embodiments are merely illustrative of individual aspects of the invention. Modifications and changes of the invention can be made without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and apparatus falling within the scope of the invention will be apparent to those skilled in the art from the foregoing description. Such modifications and changes are intended to be within the scope of the appended claims. The invention is limited only by the terms of the appended claims and the full scope of equivalents falling within the scope of the claims is also encompassed by the invention.

Claims (20)

As an active ingredient, structural formula (I):
Wherein R is hydrogen; lower alkyl having 1 to 8 carbon atoms; halogen selected from F, Cl, Br, and I; alkoxy having 1 to 3 carbon atoms; nitro group; hydroxy; trifluoromethyl And selected from the group consisting of thioalkoxy having 1 to 3 carbon atoms;
x is an integer from 1 to 3, but when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different and are each selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, and cycloalkyl having 3 to 7 carbon atoms;
R ₁ and R ₂ may combine to form a 5- to 7-membered heterocyclic ring substituted with a substituent selected from the group consisting of hydrogen, an alkyl group, and an aryl group. 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, the nitrogen atoms not being directly bonded to each other or to the oxygen atoms)
A composition for treating drug addiction comprising a therapeutically effective amount of a compound having the following formula: or a pharmaceutically acceptable salt or ester thereof , wherein the drug is nicotine, opioid, cocaine, amphetamine, methamphetamine, phencyclidine ( PCP) and at least one selected from the group consisting of methylenedioxymethamphetamine (MDMA) . The compound is
The composition according to claim 1, wherein:   The composition according to claim 1, wherein R is hydrogen and x = 1. The composition of claim 1, wherein R, R ₁ , and R ₂ are hydrogen and x = 1.   Wherein the compound having the structural formula (I) is an enantiomer substantially free of other enantiomers, or an enantiomeric mixture in which one enantiomer of the compound having the structural formula (I) is predominant. The composition according to claim 1.   6. The composition of claim 5, wherein one enantiomer comprises about 90% or more.   7. A composition according to claim 6, wherein one enantiomer comprises about 98% or more. Said enantiomer has the structural formula (Ia):
Wherein R is hydrogen; lower alkyl having 1 to 8 carbon atoms; halogen selected from F, Cl, Br, and I; alkoxy having 1 to 3 carbon atoms; nitro group; hydroxy; trifluoromethyl And selected from the group consisting of thioalkoxy having 1 to 3 carbon atoms;
x is an integer from 1 to 3, but when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different and are each selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, and cycloalkyl having 3 to 7 carbon atoms;
R ₁ and R ₂ may combine to form a 5- to 7-membered heterocyclic ring substituted with a substituent selected from the group consisting of hydrogen, an alkyl group, and an aryl group. 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, the nitrogen atoms not being directly bonded to each other or to the oxygen atoms)
The composition according to claim 5, which is a (S) or (L) -enantiomer represented by:   9. A composition according to claim 8, wherein one enantiomer comprises about 90% or more.   10. The composition of claim 9, wherein one enantiomer comprises about 98% or more. Rx, R _1, and R ₂ is hydrogen A composition according to claim 8, wherein x is 1. The enantiomer has the structural formula (Ib):
Wherein R is hydrogen; lower alkyl having 1 to 8 carbon atoms; halogen selected from F, Cl, Br, and I; alkoxy having 1 to 3 carbon atoms; nitro group; hydroxy; trifluoromethyl And selected from the group consisting of thioalkoxy having 1 to 3 carbon atoms;
x is an integer from 1 to 3, but when x is 2 or 3, R may be the same or different;
R ₁ and R ₂ may be the same or different and are each selected from the group consisting of hydrogen, lower alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, and cycloalkyl having 3 to 7 carbon atoms;
R ₁ and R ₂ may combine to form a 5- to 7-membered heterocyclic ring substituted with a substituent selected from the group consisting of hydrogen, an alkyl group, and an aryl group. 1 to 2 nitrogen atoms and 0 to 1 oxygen atoms, the nitrogen atoms not being directly bonded to each other or to the oxygen atoms)
The composition according to claim 5, which is a (R) or (D) -enantiomer represented by:   13. A composition according to claim 12, wherein one enantiomer comprises about 90% or more.   14. A composition according to claim 13, wherein one enantiomer comprises about 98% or more.   13. The composition of claim 12, wherein the enantiomer is (R)-(β-amino-benzenepropyl) carbamate.   16. The composition of claim 15, wherein the enantiomer that is (R)-(β-amino-benzenepropyl) carbamate accounts for about 90% or more.   17. The composition of claim 16, wherein the enantiomer that is (R)-(β-amino-benzenepropyl) carbamate comprises about 98% or more. Addictive drug composition of claim 1 to 17, characterized in that at least one selected f loins, and from morphine or Ranaru group. The composition according to claim 1 , wherein the drug is cocaine. 20. The composition of claims 1-19 , wherein the therapeutically effective amount of the compound is about 0.01-300 mg / kg / dose.